Harvard Medical School Study Reveals Role of Neutrophils in Cancer Immunotherapy Treatments

Researchers from Harvard Medical School, the University of Geneva, and Ludwig Cancer Research published a study last week suggesting neutrophils can play an important role in improving cancer immunotherapy outcomes.

The study, led by HMS professors Allon M. Klein and Mikael J. Pittet, found that mice and human cancer patients had different outcomes based on levels of different types of neutrophil found in their blood and tissues. The researchers published their findings on March 30 in the journal Cell.

Immunotherapy, a form of cancer treatment, aims to eliminate tumors using the body’s immune system machinery. But the varied outcomes of patients treated with immunotherapy have been a topic of ongoing scientific research.

“There are therapies that work and we don’t know why, and there are therapies that don’t work and we don’t know why,” said Nicolas A. Gort Freitas, a Ph.D. candidate in Systems, Synthetic, and Quantitative Biology who works in Klein’s lab.

Traditionally, immunotherapy utilizes the adaptive immune system — including T cells and B cells — to recognize and attack specific antigens such as tumors. Neutrophils, short-lived white blood cells in the innate immune system that circulate rapidly through the human body, have been largely overlooked by researchers due to their observed role in promoting tumor growth, according to Klein.

Gort Freitas said the study revealed “heterogeneity among neutrophils,” separating “evil” cells that contribute to tumor growth from “good” cells that combat cancer. Experiments in mice showed this latter subset of neutrophils was abundant in successful treatment. When the researchers intentionally blocked these neutrophils, however, treatment efficacy decreased.

“Every single time that a therapy succeeded in our animal experiments, we saw a large neutrophil response, and when the therapies failed we saw that the neutrophils weren’t doing too much,” Klein said.

Neutrophils are not the only cells in the innate immune system that have been misunderstood for their role in cancer progression, according to Christopher S. Garris, an assistant professor of pathology at Massachusetts General Hospital and contributor to the study.

“This happened with the macrophage. It happened with the dendritic cell, Garris said. “As we further get better techniques — like single cell RNA sequencing — to subdivide and cluster new cell populations and make distinctions, we’re going to find there’s going to be good ones and bad ones.”

Klein said the research can help improve immunotherapy treatments by activating tumor-fighting neutrophils in patients in conjunction with interferon therapy.

“These neutrophils, they look like they have a pattern which shows that they’re responding to a particular signaling molecule called interferon,” Klein said. “Interferon is an immune modulator molecule, so combining different types of immunotherapies could simultaneously activate the T cells.”

While the findings of the study are promising, Klein said it is “an absolute imperative” to continue research of neutrophils in humans.

“At this point, we just know that they’re important,” said Klein. “But the precise way in which they act, we’ve only really sketched out in some very broad outlines.”

Klein said he believes scientists should take a more holistic approach to cancer treatments.

“There is already active attention on how to bring the innate immune system into the story more closely,” said Klein. “I suspect that there’ll now be even more attention on how to bring neutrophils into immunotherapy and to target neutrophils specifically.”